Abstract
Alzheimer’s disease (AD) is characterized by extensive neuron loss that accompanies profound impairments in memory and cognition. We examined the neuronally directed effects of the retinoid X receptor agonist bexarotene in an aggressive model of AD. We report that a two week treatment of 3.5 month old 5XFAD mice with bexarotene resulted in the clearance of intraneuronal amyloid deposits. Importantly, neuronal loss was attenuated by 44% in the subiculum in mice 4 months of age and 18% in layer V of the cortex in mice 8 months of age. Moreover, bexarotene treatment improved remote memory stabilization in fear conditioned mice and improved olfactory cross habituation. These improvements in neuron viability and function were correlated with significant increases in the levels of post-synaptic marker PSD95 and the pre-synaptic marker synaptophysin. Moreover, bexarotene pretreatment improved neuron survival in primary 5XFAD neurons in vitro in response to glutamate-induced excitotoxicity. The salutary effects of bexarotene were accompanied by reduced plaque burden, decreased astrogliosis, and suppression of inflammatory gene expression. Collectively, these data provide evidence that bexarotene treatment reduced neuron loss, elevated levels of markers of synaptic integrity that was linked to improved cognition and in an aggressive model of AD.
Highlights
Alzheimer’s disease (AD) is a highly prevalent disorder characterized by progressive cognitive impairment associated with the accumulation of amyloid beta (Aβ) within the brain and subsequent development of neuronal dystrophy and death
We examined APLP2, a protein related to amyloid precursor protein (APP) but not overexpressed in this mouse model
We report that bexarotene improves neuron survival and reduces intraneuronal APP/Aβdeposition in an aggressive mouse model of Alzheimer’s disease
Summary
Alzheimer’s disease (AD) is a highly prevalent disorder characterized by progressive cognitive impairment associated with the accumulation of amyloid beta (Aβ) within the brain and subsequent development of neuronal dystrophy and death. In experimental models of AD, treatment with nuclear receptor agonists results in improved cognition and memory and attenuation of the disease-related pathology[1]. The 5XFAD transgenic mice exhibit intraneuronal deposits of amyloid precursor protein (APP), and its processing products, including Aβpeptides (hereafter termed APP/Aβ). These intraneuronal accumulations of APP/Aβappear in neurons in layer V and the subiculum of 5XFAD mice early in disease pathogenesis before extracellular plaques form[16,17]. These mice have robust neuritic dystrophy, extracellular amyloid deposition, and gliosis. We have recapitulated bexarotene-dependent plaque removal in the 5XFAD mice
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